Peripheral neuropathy is the most common neurological complication of HIV-1 infection, affecting over onethird of infected individuals including those treated with antiretroviral therapy. The paradoxical increased incidence of peripheral neuropathy seen in HIV-infected patients following widespread use of HAART regimens reflects the additive effects of HIV-induced PNS damage and anti-retroviral neurotoxicity. Our extensive studies in SIV-infected macaques have detailed PNS damage closely resembling HIV-induced PNS disease; these findings set the stage for also examining neurotoxic damage caused by HAART regimens in the SIV/macaque model. Our follow-up studies have shown significant epidermal nerve fiber loss in SIV-infected macaques on HAART. Thus, despite suppression of viral replication, peripheral nerve damage still develops in SIV-infected macaques treated with HAART. This finding establishes a valuable SIV/macaque model for studying the mechanisms underlying peripheral nervous system damage caused by HIV and antiretroviral therapy. In studies focused on groups of animals including A) uninfected controls, B) SIV-infected, 3) SIV-infected HAART-treated, and 4) uninfected animals receiving HAART, we have three aims: 1) To determine whether HAART treatment that effectively controls SIV replication nonetheless exacerbates SIV-induced slowing of nerve conduction in small sensory nerve fibers (C-fibers), 2) To determine whether administration of HAART in SIV infection and independent of viral infection induces mitochondrial dysfunction in the PNS and 3) To determine whether administration of HAART impairs nerve regeneration in SIV infection (and independently of infection) using our macaque intracutaneous axotomy model of nerve regeneration. These proposed studies in the SIV/macaque HAART model will enable us to dentify the specific contributions to PNS damage attributable to virus versus neurotoxic HAART regimens.